Remote ischemic preconditioning (RIPC) is a clinically effective and non-invasive ischemia-reperfusion (I/R) of a remote organ that provides significant protection against more acute I/R. However, the specific protective factor released by RIPC or the mechanism of RIPC-mediated protection remains elusive so far. Further, the understanding by which the RIPC released factor confers protection to the heart in I/R remains unclear. We have identified Neuregulin (Nrg1?) as one of the RIPC factors that is required for conferring protection to the myocardium in I/R. Our proposed studies will uncover and endothelial mechanism that RIPC-mediated Nrg1? utilizes to provide protection in I/R injury. We will test the hypothesis that RIPC-mediated release of Nrg1? protects coronary endothelial dysfunction by interacting with its receptor ErbB2 expressed in endothelial cells, and this endothelial Nrg1?-ErbB2 interaction induces survival signaling resulting in protection against myocardial ischemia-reperfusion injury. Our hypothesis is novel and intriguing as endothelial Nrg1? is believed to interact with ErbB2 expressed on cardiomyocytes. Our studies will investigate for the first time the role of Nrg1?-ErbB2 in the coronary endothelium that elicits survival pathway to protect myocardium in I/R. In our aim 1, we will determine the mechanism of RIPC mediated release of Nrg1? that is required for protection against MI; Aim 2) we will determine mitochondrial redox mechanism induced due to protection ErbB2 degradation and its role in protection against coronary endothelial dysfunction due to I/R; Aim 3) the role of RIPC ?mediated rescue of ErbB2 and resultant decrease in ROS in protection against endothelial dysfunction, myocardial I/R will be determined. We will use novel mouse model with specific deletion of ErbB2 in the endothelial cells to understand the specific role of endothelial ErbB2 in RIPC-dependent protection of myocardium in I/R. We will use state-of-the art experimental methodology such as proximity ligation assays, pressure and wire myography, echocardiography and molecular and biochemical approaches to delineate the precise role of RIPC-mediated Nrg1? in protection against MI.